Author and Reporter: Ritu Saxena, Ph.D.
Mitochondria is an important cell organelle that is associated with several key cellular functions as energy production, anabolism, calcium homeostasis and cell programmed death, and any abnormalities occurring in mitochondria would lead to alteration of normal cellular function.
Role of mitochondria in cancer has long been implicated. Post published on September 1, 2012 (https://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/) presents a brief overview of the mechanisms by which mitochondrial defects could be associated with cancer. Different studies on various types of Cancers have tried to determine the mtDNA mutations and the mechanisms involved. An important aspect of cancerous progression is the cancer cell migration and it has been observed that mitochondrial dysfunction is involved in cancer cell migration. However, the molecular mechanism still needs to be deciphered.
A group from Taiwan recently published their findings in the Biochimica et Biophysica Acta journal stating that enhanced β5-integrin expression was involved in promoting cell migration in human gastric cancer cell line as a result of mitochondrial dysfunction.
The authors used human gastric cancer cell line, SC-M1 cells for their studies. The methodology followed was to first create mitochondrial dysfunction in the SC-M1 cells by the use of oxidative phosphorylation inhibitors: oligomycin (Complex V inhibitor) and antimycin A (Complex III inhibitor) thereby inhibiting mitochondrial function. The results indicated that impaired oxidative phosphorylation caused an increase in the intracellular Reactive Oxygen Species (ROS) that lead to an increased cell migration in SC-M1 cells.
Different types of integrin molecules have been implicated in cell migration. Hung et al extracted RNA and protein from SC-M1 cells in order to study the different types of integrins, and observed that the levels of β5-integrin were significantly upregulated in SC-M1 cells. Simultaneously, the surface expression of the dimer- β5-integrin and αv-integrin, was studied in cancer cells with using FACS. The analysis revealed a higher surface expression of the dimer corresponding to the higher levels of the protein and RNA results of β5-integrin expression in SC-M1 cells with mitochondrial dysfunction. Infact, a subpopulation of SC-M1 cells that showed higher migration capability (SC-M1-3rd) was observed to harbor a higher lever of β5-integrin expression, correlating β5-integrin expression with cell migration ability. The experiments supported the role of β5-integrin in cell migration in gastric cancer cells.
Finally, authors confirmed the in vitro results in the human gastric cancer samples. Immunohistochemical analysis revealed that β5-integrin was stained positive in around 73% of the cancer samples. Additionally, the higher expression levels of β5-integrin could be correlated with the invasive ability and more aggressive behavior of gastric cancer cells.
Authors stated “our study pinpoints another aspect that links the induction of intracellular ROS level in mitochondrial dysfunction gastric cancer cells with the activation of αvβ5-integrin. Taken together, the induction of β5-integrin is important to gastric cancer metastasis, especially in cancer cells that exhibit mitochondrial dysfunction.”
Thus, blockage of αvβ5-integrin function by antibodies might be tested as a potential therapy for preventing or delaying gastric cancer metastasis, especially in gastric cancers harboring mitochondrial dysfunction.
Sources:
Research article: http://www.ncbi.nlm.nih.gov/pubmed?term=22561002
Related posts: https://pharmaceuticalintelligence.com/2012/09/01/mitochondria-and-cancer-an-overview/
https://pharmaceuticalintelligence.com/2012/08/14/detecting-potential-toxicity-in-mitochondria/
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GREAT WORK, Ritu.
How about the category: Human Immune System?
Yet another association of vitronectin-binding integrin (alphaV-containing) upregulation in metastatic cancer. Please also see and incorporated references: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0036753
Gastric cancer is rare in the Western hemisphere, but not so rare in Japan. The most aggressively invasive is LINITIS PLASTICA, which goes through the wall and plasters the epigastric peritoneum. This type of invasion would be similar to ovarian caking of the peritoneum. I have not thought about it since my mothers death.
The incidence is not as rare as 40 years ago. It was surmised that there is an association with grill type cooking. There are a few points to think about:
1. Mitochondrial association should tend to be maternal transmission, which I’m not sure is the case. More likely, I would think that it is EPIgenetic.
2. There should be a relationship to prolonged high stress, which would have an effect in disrupting the immune system and increasing ROS. This is beyond what we know about it.
3. This finding could enable pathology diagnosis with histological staining. But I don’t see how early diagnosis will be possible in this case.
Larry, thanks for the comment. You have raised some very important points about Gastric Cancer. Litinits plastica, as you suggested is a more invasive form of gastric cancer so according to the report, there might be a correlation between the invasive nature of the cells and their integrin levels. Therefore, it it might be interesting to look at the beta5-integrin levels in the tissue samples through immunostaining.
There could definitely be a relationship to prolonged stress leading to ROS production, even in the case of mitochondria. Somatic mutations caused due to stress in any form would, I suppose, lead to disruption of mitochondrial function and in case it leads to ROS production, there could be several pathways activation consequently resulting in cancerous cells.
Also, I doublt that immunohistochemcial staining of beta5 integrin could be used as a pathological diagnosis method of gastric cancer. It might be a good indicator of later stages of cancer progression including metastasis. However, I could be wrong as integrins have been all over the place.
Ritu
Thank you for your comment.
Please reply to Meg’s comment above, please.
I agree with Larry, it seems epigenetics.
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Very interesting the conundrum of ROS signaling in the cancer cell. I would be very interested to know how increased ROS signals an increased expression of integrin. I wonder if further studies have shown the mechanism? In addition is this a signal from mito generated ROS or ROS in general (i.e. if you added in peroxide or hydroquinone (exogenous) does this increase integrin signaling? I wonder, given your earlier post about fusion/fission if there is a mito factor we don’t know about yet that can take a mito generated ROS signal to the nucleus to regulate gene expression? Thanks